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Improving the Positive Predictive Value of Non-Invasive Prenatal Screening (NIPS)

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ABSTRACT

We evaluated performance characteristics of a laboratory-developed, non-invasive prenatal screening (NIPS) assay for fetal aneuploidies. This assay employs massively parallel shotgun sequencing with full automation. GC sequencing bias correction and statistical smoothing were performed to enhance discrimination of affected and unaffected pregnancies. Maternal plasma samples from pregnancies with known aneuploidy status were used for assay development, verification, and validation. Assay verification studies using 2,085 known samples (1873 unaffected, 69 trisomy 21, 20 trisomy 18, 17 trisomy 13) demonstrated complete discrimination between autosomal trisomy (Z scores >8) and unaffected (Z scores <4) singleton pregnancies. A validation study using 552 known samples (21 trisomy 21, 10 trisomy 18, 1 trisomy 13) confirmed complete discrimination. Twin pregnancies showed similar results. Follow-up of abnormal results from the first 10,000 clinical samples demonstrated PPVs of 98% (41/42) for trisomy 21, 92% (23/25) for trisomy 18, and 69% (9/13) for trisomy 13. Adjustment for causes of false-positive results identified during clinical testing (eg, maternal duplications) improved PPVs to 100% for trisomy 21 and 96% for trisomy 18. This NIPS test demonstrates excellent discrimination between trisomic and unaffected pregnancies. The PPVs obtained in initial clinical testing are substantially higher than previously reported NIPS methods.

No MeSH data available.


Ideogram for chromosome 22 from a patient with a fetal microdeletion                            in the DiGeorge region.
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pone.0167130.g008: Ideogram for chromosome 22 from a patient with a fetal microdeletion in the DiGeorge region.

Mentions: Of 5 cases positive for 47,XXX, 2 have follow-up information; both were confirmed to have that karyotype. Two cases were positive for Klinefelter syndrome, and the single fetal genotype we obtained confirmed the 47,XXY karyotype. Only one sample was positive for 47,XYY, but follow-up information was unavailable. We had only one case involving microdeletion in the DiGeorge region of chromosome 22 (Fig 8). The DiGeorge-specific Z score was -7. Amniocentesis confirmed the abnormality. Two samples had 2 abnormalities: 1 with trisomy 21 and Turner syndrome that miscarried and the other with high risk for both trisomy 21 and 18, for which we have not received follow-up data.


Improving the Positive Predictive Value of Non-Invasive Prenatal Screening (NIPS)
Ideogram for chromosome 22 from a patient with a fetal microdeletion                            in the DiGeorge region.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382935&req=5

pone.0167130.g008: Ideogram for chromosome 22 from a patient with a fetal microdeletion in the DiGeorge region.
Mentions: Of 5 cases positive for 47,XXX, 2 have follow-up information; both were confirmed to have that karyotype. Two cases were positive for Klinefelter syndrome, and the single fetal genotype we obtained confirmed the 47,XXY karyotype. Only one sample was positive for 47,XYY, but follow-up information was unavailable. We had only one case involving microdeletion in the DiGeorge region of chromosome 22 (Fig 8). The DiGeorge-specific Z score was -7. Amniocentesis confirmed the abnormality. Two samples had 2 abnormalities: 1 with trisomy 21 and Turner syndrome that miscarried and the other with high risk for both trisomy 21 and 18, for which we have not received follow-up data.

View Article: PubMed Central - PubMed

ABSTRACT

We evaluated performance characteristics of a laboratory-developed, non-invasive prenatal screening (NIPS) assay for fetal aneuploidies. This assay employs massively parallel shotgun sequencing with full automation. GC sequencing bias correction and statistical smoothing were performed to enhance discrimination of affected and unaffected pregnancies. Maternal plasma samples from pregnancies with known aneuploidy status were used for assay development, verification, and validation. Assay verification studies using 2,085 known samples (1873 unaffected, 69 trisomy 21, 20 trisomy 18, 17 trisomy 13) demonstrated complete discrimination between autosomal trisomy (Z scores >8) and unaffected (Z scores <4) singleton pregnancies. A validation study using 552 known samples (21 trisomy 21, 10 trisomy 18, 1 trisomy 13) confirmed complete discrimination. Twin pregnancies showed similar results. Follow-up of abnormal results from the first 10,000 clinical samples demonstrated PPVs of 98% (41/42) for trisomy 21, 92% (23/25) for trisomy 18, and 69% (9/13) for trisomy 13. Adjustment for causes of false-positive results identified during clinical testing (eg, maternal duplications) improved PPVs to 100% for trisomy 21 and 96% for trisomy 18. This NIPS test demonstrates excellent discrimination between trisomic and unaffected pregnancies. The PPVs obtained in initial clinical testing are substantially higher than previously reported NIPS methods.

No MeSH data available.